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Current literature finds females have improved outcomes over their male counterparts after severe traumatic brain injury (TBI), while the opposite seems to be true for mild TBI. This begs the question as to what may be driving these sex differences after TBI. Estrogen is thought to be neuroprotective in certain diseases, and its actions have been shown to influence mitochondrial function. Mitochondrial impairment is a major hallmark of TBI, and interestingly, this dysfunction has been shown to be more severe in males than females after brain injury. This suggests estrogen could be playing a role in promoting "mitoprotection" following TBI. Despite the existence of estrogen receptors in mitochondria, few studies have examined the direct role of estrogen on mitochondrial function, and no studies have explored this after TBI. We hypothesized ex vivo treatment of isolated mitochondria with 17β-estradiol (E2) would improve mitochondrial function after experimental TBI in mice. Total mitochondria from the ipsilateral (injured) and contralateral (control) cortices of male and female mice were isolated 24 h post-controlled severe cortical impact (CCI) and treated with vehicle, 2 nM E2, or 20 nM E2 immediately before measuring reactive oxygen species (ROS) production, bioenergetics, electron transport chain complex (ETC) activities, and β-oxidation of palmitoyl carnitine. Protein expression of oxidative phosphorylation (OXPHOS) complexes was also measured in these mitochondrial samples to determine whether this influenced functional outcomes with respect to sex or injury. While mitochondrial ROS production was affected by CCI in both sexes, there were other sex-specific patterns of mitochondrial injury 24 h following severe CCI. For instance, mitochondria from males were more susceptible to CCI-induced injury with respect to bioenergetics and ETC complex activities, whereas mitochondria from females showed only Complex II impairment and reduced β-oxidation after injury. Neither concentration of E2 influenced ETC complex activities themselves, but 20 nM E2 appeared to uncouple mitochondria isolated from the contralateral cortex in both sexes, as well as the injured ipsilateral cortex of females. These studies highlight the significance of measuring mitochondrial dysfunction in both sexes after TBI and also shed light on another potential neuroprotective mechanism in which E2 may attenuate mitochondrial dysfunction after TBI in vivo.